Turning up the heat on COVID-19: heat as a therapeutic intervention

Enveloped viruses such as SAR-CoV-2 are sensitive to heat and are destroyed by temperatures tolerable to humans. All mammals use fever to deal with infections and heat has been used throughout human history in the form of hot springs, saunas, hammams, steam-rooms, sweat-lodges, steam inhalations, hot mud and poultices to prevent and treat respiratory infections and enhance health and wellbeing. This paper reviews the evidence for using heat to treat and prevent viral infections and discusses potential cellular, physiological and psychological mechanisms of action. In the initial phase of infection, heat applied to the upper airways can support the immune system’s first line of defence by supporting muco-ciliary clearance and inhibiting or deactivating virions where they first lodge. This may be further enhanced by the inhalation of steam containing essential oils with anti-viral, mucolytic and anxiolytic properties. Heat applied to the whole body can further support the immune system’s second line of defence by mimicking fever and activating innate and acquired immune defences and building physiological resilience. Heat-based treatments also offer psychological benefits and enhanced mental wellness by focusing attention on positive action, enhancing relaxation and sleep, inducing 'forced-mindfulness', and invoking the power of positive thinking and ‘remembered wellness’. Heat is a cheap, convenient and widely accessible therapeutic modality and while no clinical protocols exist for using heat to treat COVID-19, protocols that draw from traditional practices and consider contraindications, adverse effects and infection control measures could be developed and implemented rapidly and inexpensively on a wide scale. While there are significant challenges in implementing heat-based therapies during the current pandemic, these therapies present an opportunity to integrate natural medicine, conventional medicine and traditional wellness practices, and support the wellbeing of both patients and medical staff, while building community resilience and reducing the likelihood and impact of future pandemics.


Heat in viruses and mammals
Life exists within a narrowly defined temperature range, yet viruses, which are not technically alive, can remain biologically active in a wide range of environments. Enveloped viruses, such as rhinoviruses and coronaviruses, are most active in cool dry conditions, which are associated with increased occurrence of respiratory tract infections (Mäkinen et al., 2009), including infections with SARS-CoV (Chan et al., 2011) andSAR-CoV-2 (Sajadi et al., 2020;Wang et al., 2020). While enveloped viruses can remain active for long periods in cold conditions, their lipid envelopes are destroyed by temperatures tolerable to humans. The heat sensitivity of viruses is used routinely to deactivate viruses within vaccines, and temperatures of 55 to 65°C for 15 to 30 minutes are reported to deactivate a range of enveloped viruses, including coronaviruses (Darnell et al., 2004;Duan et al., 2003;Hu et al., 2011;Kampf et al., 2020;Lelie et al., 1987;WHO Report, 2003).
The first line of defence against respiratory viruses is the nasal cavity and sinuses, which maintains a protective mucosal barrier that allows viruses to be trapped, identified by the immune system and swept away, as well as serving an important thermoregulatory role. The nasal cavity and sinuses in humans constantly exchanging heat with inhaled air through convection, conduction and evaporation, which serves to cool inhaled air in summer and warm and humidify air in winter (Soni & Nayak, 2019). The upper airways also serve as the first line of defence against respiratory viruses by maintaining a protective mucosal barrier that filters and traps foreign particles and pathogens in a layer of watery mucus, and enables them to be identified by the immune system. This mucus is then moved by cilia towards the pharynx, where it is either swallowed or expelled by coughing, sneezing and nose blowing. A moist mobile mucosal barrier is vital in the defence against respiratory infections and this barrier is enhanced by warm humid conditions and impaired by cigarette smoke and particulate pollution (Fahy & Dickey, 2010).
In winter when sunlight is restricted and the air is cold and dry, the nasal cavity becomes the coldest part of the body and if the airways dry out and the mucous becomes thicker and more difficult to clear, conditions become more favourable for viral penetration and replication. The ability of cool, dry conditions to enhance viral infection has been demonstrated in mice, with humidity of around 20% being shown to slow muco-ciliary clearance, impair innate antiviral defence, and reduce tissue repair function, leading to more rapid and severe illness compared with humidity of 50% (Kudo et al., 2019).
If respiratory viruses get past the first line of defence, fever is produced as part of the acute phase response, which forms the immune system's second line of defence. Fever is a cardinal response to infection that has been conserved within vertebrates for more than 600 million years. Ectotherms as diverse as reptiles, fish, and insects raise their core temperature during infection through behavioural regulation, and all mammals have evolved sophisticated mechanisms to create and disperse heat and manage the oxidative stress associated with operating at higher temperatures (Evans et al., 2015).

Heat as medicine
The use of heat for cleansing and healing is a conscious extension of mammals' use of heat that has been practiced throughout human history. Hot springs, saunas, hammams, steam rooms, sweat lodges, steam inhalations, baths, hot mud and poultices have been used traditionally in cold, dry climates to prevent and treat respiratory infections and to enhance overall health and wellbeing. Heat-based therapies are not widely used in mainstream medicine, other than the local application of hot packs for symptomatic relief, or the use of novel technologies such as microwaves, radiofrequency energy, ultrasound, infrared radiators, ferromagnetic seeds, nanoparticles and resistive implants that apply heat to treat various cancers (Chicheł et al., 2007). Heat-based treatments however, are standard offerings in wellness establishments, such as hot springs, bathing facilities, gymnasiums, fitness centers, hotels and resorts, where they are used for both therapy and recreation (Clark-Kennedy & Cohen, 2017).
There are multiple lines of evidence to support the use of heat and humidity for the prevention and treatment of viral respiratory infections. Historical and emerging evidence suggests regular sauna bathing enhances cardiovascular, respiratory and immune function as well as improving mood and quality of life (Hussain & Cohen, 2018)(Laukkanen et al., 2018. Finnish sauna bathing, which involves brief exposures to high environmental temperature (80°C-100°C) has been shown to reduce the risk of all-cause mortality, sudden cardiac death, cardiovascular disease and vascular diseases such as high blood pressure and stroke, along with the risk of neurocognitive diseases, skin conditions and painful conditions such as rheumatic diseases and headache (Laukkanen et al., 2015;Laukkanen et al., 2018;Laukkanen & Kunutsor, 2019). Epidemiological evidence further suggests that frequent sauna bathing is associated with a reduced risk of pneumonia and viral infection (Kunutsor et al., 2017a) (Kunutsor et al., 2017aKunutsor et al., 2017b), and randomised controlled trial evidence suggests that regular saunas can halve the incidence of respiratory viral infections (Ernst et al., 1990). Randomised controlled trials further suggest hot air can treat respiratory infections with humidified air at temperatures above 43°C for 20 to 30 minutes being found to reduce viral shedding, provide immediate relief of symptoms and improve the course of the common cold (Tyrrell, 1988;Tyrrell et al., 1989).

Amendments from Version 1
The paper has been revised in response to reviewer suggestions and additional references on the changes in health outcomes and cardiorespiratory function with sauna bathing have been added. Further information on the use of heat to treat cancer and general adverse effects and safety information has also been added. Some sections have been moved to provide a more cohesive flow of information and some wording has been changed to enhance readability, better distinguish between fever and hyperthermia, and maintain a focus on the use of heat to treat viral infectiosn such as COVID-19.

Mechanisms of action
The mechanisms by which heat overcomes viral infections depends on the setting, source, temperature, humidity, location and time course of applied heat. Whether internally generated or externally applied, heat has a profound influence on host defences and physiological resilience, as well as on viral load and virulence, and engages adaptive thermoregulatory mechanisms that can increase or decrease body temperature in order to restore homeostasis (Schieber & Ayres, 2016).
Hyperthermia and heat stress have multiple actions that may help mitigate viral infections. These include direct inhibition of pathogens, stimulation of both the innate and adaptive arms of the immune system and activation of regulatory processes that dampen inflammatory responses and prevent excessive tissue damage (Evans et al., 2015). Inhalation of hot air supports the immune system's first line of defence by direct inhibition or deactivation of virions in the upper airways where they first lodge. Inhalation of hot humid air also supports muco-ciliary clearance, which can be further enhanced by inhalation of steam (Gujrathi et al., 2016). Heat applied to the whole body further supports the immune system's second line of defence by inducing heat-stress that mimics the effects of fever (Schieber & Ayres, 2016).
Febrile temperatures activate multiple cellular responses that include complex reciprocal regulation between immune system activation, inflammation and the heat shock response pathway (Singh & Hasday, 2013). While the mechanisms by which heat-stress modulates immune function are not fully understood, higher temperatures have been shown to activate immune cells by making their cell membranes more fluid, which increases cell differentiation and activation by viral antigens and enables a faster and more effective response to viral threats (Mace et al., 2011).
Acute heat stress has been shown to increase the TNF-alpha response of monocytes (Zellner et al., 2002), enhance interleukin-2 induced activity of Natural Killer (NK) cells (Kappel et al., 1991), and cause a 10-fold increase in interferon-γ production by T-lymphocytes (Downing et al., 1988) while regular heat-stress has been shown to reduce adrenaline and cortisol, increase the cytotoxicity of NK cells, and enhance the proliferative response of B cells (Tomiyama et al., 2015). Heat-stress also stimulates the release of Heat Shock Proteins (HSPs), (Iguchi et al., 2012) which play an important role in antigen presentation and crosspresentation, activation of macrophages and lymphocytes, and activation and maturation of dendritic cells (Tsan & Gao, 2009) as well as serving a chaperone function and protecting immune cells and proteins from heat-induced damage (Singh & Hasday, 2013). The immunostimulatory effects of heat stress on the innate immune system may be further enhanced by alternating heat exposure with exposure to cold (Heinonen & Laukkanen, 2018), which leads to leukocytosis, granulocytosis, an increase in NK cell count and activity, and an elevation in circulating levels of IL-6 (Brenner et al., 1999).
In addition to enhancing cellular responses, heat-stress induces a hormetic stress response that builds physiological resilience and confers tolerance to subsequent stress in a similar way to exercise (Gálvez et al., 2018). Heat stress improves respiratory function by reducing pulmonary congestion and increasing tidal volume, vital capacity, ventilation, and forced expiratory volume of the lungs (Laitinen et al., 1988), and improves cardiovascular function by modulating the autonomic nervous system, reducing inflammation, oxidative stress and blood pressure, increasing cardiac output, plasma volume and peripheral blood flow, and improving endothelial function, lipid profile and arterial compliance (Heinonen & Laukkanen 2018;Kunutsor et al., 2018;Laukkanen et al., 2018;Laukkanen & Kunutsor, 2019). Heat stress also aids in detoxification via sweating (Crinnion, 2011) through which some toxic elements are preferentially excreted (Genuis et al., 2011). Furthermore, when heat stress is followed by cold exposure, blood is shunted to the internal organs, which induces a diuresis (Epstein, 1978), and further aids in detoxification (Cochrane, 2004).
Heat-stress may offer a further advantage against respiratory viral infections by altering blood pH through hyperthermiainduced hyperventilation and subsequent respiratory alkalosis (Tsuji et al., 2016), which creates alkaline conditions that may be more favourable to host defenses. The ability of a transient alkaline environment to inhibit viral replication and reduce infectivity has been demonstrated with human coronavirus 229E, which has maximal infectivity in acid conditions (Lamarre & Talbot, 1989), and with coronavirus MHV-A59, which undergoes conformational changes in the spike glycoprotein at a pH of 8 at 37°C degrees and leads to rapid and irreversible inactivation and loss of infectivity (Sturman et al., 1990).
In addition to offering physiological advantages in the battle against viral infection such as COVID-19, heat-based treatments can support mental wellness and confer many psychological benefits. Sauna bathing and other forms of heat therapy require time and effort devoted towards active relaxation that can help divert attention from anxiety-producing news and/or relieve boredom associated with social confinement. Sauna bathing also enhances sleep (Hussain et al., 2019), which further supports immune function (Irwin & Opp, 2017). Engaging in an activity with an intended positive outcome can also impart feelings of control that may otherwise be lacking, and doing something that feels good and having positive expectations elicits the power of positive thought and the placebo effect or 'remembered wellness' (Benson & Friedman, 1996). Furthermore, the exploration of heat-tolerance induces a 'forced-mindfulness' and a focus on the breath, which has additional physical and psychological benefits (Black & Slavich, 2016). In a time of social distancing, saunas can also provide a way for close family members to come together in ways that have supported family cohesion for generations in Finland and other Nordic countries (Mather & Kaups, 1963).

Clinical applications and implications
There are a range of heat-based interventions that can be used alongside other personal hygiene measures to aid in overcoming COVID-19. For example, warming and humidifying indoor environments can prevent drying of the nasal mucosa, increase muco-ciliary clearance and nasal patency, and provide symptomatic relief (Ophir & Elad, 1987). The direct application of heat to the upper airways, routinely or at the first signs of infection, may further serve to inhibit or deactivate virions in the place where they first lodge. This has been demonstrated in vitro with temperatures of 45°C for 20 minutes activating immune cells, releasing HSPs and suppressing rhinovirus multiplication by more than 90% (Conti et al., 1999). The inhalation of steam with added essential oils with anti-viral, decongestant, anxiolytic and other properties, may further assist in facilitating muco-ciliary clearance and reducing viral load as well as providing physical and psychological relief (Ali et al., 2015;Lee et al., 2017).
Inducing mild heat-stress through the use of hot springs (balneotherapy), hot baths, saunas, steam-rooms and application of hot mud (pelotherapy), can be used to mimic fever and activate immune defenses. Enhanced immunity has been demonstrated with hyperthermia induced by traditional Finnish saunas (Pilch et al., 2013), far-infrared saunas (Sobajima et al., 2018), heated nano-mist (Tomiyama et al., 2015), hot baths (Downing et al., 1988;Kappel et al., 1991;Tsuchiya et al., 2003;Zellner et al., 2002) and geothermal mineral water (Uzunoglu et al., 2017). The beneficial effects of heat-stress may be further potentiated by the traditional practice of alternating heat with exposure to cold, which may translate into greater resistance to viral infections as evidenced by a randomised controlled trial that found regular hot and cold showers reduced work absenteeism during an influenza outbreak (Buijze et al., 2016).
In recent years far-infrared (FIR) saunas have been used as an alternative to the traditional Finnish saunas. These saunas use infrared emitters without water or added humidity and generally run at lower temperatures than Finnish saunas. While the use of FIR saunas to treat viral infection has not been studied, FIR radiation is reported to deactivate single-strand RNA viruses (Huang & Li, 2020) and FIR saunas have been shown to raise body temperature, induce hormetic stress responses and support host defenses (Shemilt et al., 2019). FIR saunas, along with other heatbased technologies may therefore also prove useful in treating patients with COVID-19.
There are currently no clinical protocols for using heat in the treatment of COVID-19, yet heat has a long history of traditional use, and traditional practices such as alternating hot and cold immersions, post-heat relaxation and use of essential oils can inform their development. While sauna bathing is generally well tolerated, heat-based clinical protocols are needed to design future studies and inform clinical practice in order to minimise the risk of cross-infection and reduce the incidence of adverse effects, which can range from burns, cramps, dizziness and fainting, to heat exhaustion, heat stroke and death. Such protocols must therefore consider contra-indications such as unstable angina, severe infection or high fever (Hannuksela & Ellahham, 2001) along with factors such as age, weight, fitness, hydration status, co-morbidities and the use of alcohol or prescription drugs (Leyk et al., 2019). Hydro-therapy treatment plans also need to consider timing, temperature and humidity, as water is 25 times more conductive than air, making steam rooms tolerable at temperatures around 50°C while dry saunas are tolerated at temperatures above 100°C.
While the clinical application of heat has promise in the prevention and treatment of COVID-19, there are significant challenges in implementing heat-based therapies. The current pandemic has seen the fear of infection lead to the widespread closure of public facilities such as bathing facilities, commercial hot springs, spas, gymnasiums, hotels and fitness centers that offer saunas and heat treatments, and while some countries such as Finland have a large number of private saunas, in most other locations private sauna ownership is limited to people with high socio-economic status. Thus, if sauna bathing is to be widely implemented, public bathing and sauna facilities will need to re-open and adopt infection control measures similar to those for dealing with COVID-19 in other public facilities (Liang, 2020).
Heat is one of oldest forms of microbial control and still remains one of the most common methods for controlling and eradicating pathogens. The temperatures achieved within a sauna are well within the range required for pathogen control and often exceed temperatures of 60°C for 30 min, 65°C for 15 min or 80°C for 1 min, which have been shown to reduce coronavirus infectivity by at least 4 log10 (Kampf et al., 2020). While the temperatures, humidity and times required to specifically deactivate SAR-CoV-2 in vivo are yet to be determined, the temperature within a sauna makes risk of cross infection in public sauna facilities highly unlikely. Strategies for limiting cross infection have been recently developed for re-opening some of the 3000 hot springs that were recently closed in China (Wang, 2020). There are also moves to reopen facilities as quarantine zones where people can undergo heat treatments during isolation or as places of respite for overworked medical staff. It may also be possible for saunas and steam rooms to be included within hospitals and rehabilitation facilities for use by both patients and staff. Furthermore, simple home-based protocols can provide guidance on using heat for people who are currently self-isolated in their homes or in quarantine. Such protocols could be evaluated using crowdsourced, citizen-science platforms, which may help to develop, test and optimize treatment strategies for current and future pandemics.

Conclusion
Heat is a cheap, convenient and widely accessible therapeutic modality with a long history of traditional use, yet it remains to be seen if heat can be effective in the treatment or prevention of COVID-19. The relatively low cost and wide availability of heat-based treatments, along with multiple mechanisms of action that include both physical and psychological dimensions, makes heat an attractive option for combating viral infections. The integration of these ancient forms of treatment with modern technology may lead to a greater integration of natural therapies in mainstream healthcare, with the potential to support the wellbeing of both patients and medical staff. This may also lead to a greater convergence between the healthcare and wellness industries, and the development of systems and activities that build the wellbeing and resilience of the wider community, thereby reducing the impact of future pandemics.

Data availability
No data is associated with this work.
You should discuss more with the lights of many published original studies on sauna and its protective health effects. The literature review of this narrative has missed many recent papers on this topic. Please consider adding the recently published key references on sauna and health outcomes so that this article would be more up-to-date. [ref-3 What is the role of improved hygiene control due to regular sauna bathing?
Warm and cold has any effect on the results?
You could add studies that may indicate that sauna is related to inflammatory markers or cytokines.

Are all factual statements correct and adequately supported by citations? Yes
Are arguments sufficiently supported by evidence from the published literature? Yes

Are the conclusions drawn balanced and justified on the basis of the presented arguments? Yes
No competing interests were disclosed. Competing Interests: Reviewer Expertise: Immunology; Thermal stress; hyperthermia, anti-tumor immunity; Stress I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard.

Version 1
Reader Comment 24 Jun 2020 , Weizmann Institute of Science, Chemical and Biological Physics, Israel

Shahar Seifer
The arguments in this article are solid, especially on account of the article of Soni & Nayak and the data on SARS-Cov-2 virus. The world is missing the simple fact that this fragile virus can be defeated by a simple mean of thermal treatment on the initial stage of the disease, before the patient is hospitalized. The author did a great literature survey, yet there are more relevant articles that describe the mechanism of action and experiments with hot air breathers. Certainly anyone who experienced spa treatment can appreciate its powerful effect on the body and mind. If logistically such treatment is unattainable for corona carriers we might encourage household medical devices for such purpose. Caution is required, since excessive heat can also increase inflammation several days after the treatment, which may increase the cytokine storm. Hence exposure should be gradual, and the mechanism of thermotolerance may be an important factor in such treatment.
Competing interests: none Competing Interests: